For several decades nitroglycerin has been administered to humans as a vasodilating agent in the treatment of cardiovascular disease. It has been shown that nitroglycerin so administered is converted in the body to nitric oxide which is the pharmacologically active metabolite. Recently, nitric oxide has been shown to be formed enzymatically as a normal metabolite from arginine in vascular endothelium to provide an important component of endothelium-derived relaxing factors (EDRFs) which are currently being intensively studied as participating in regulation of blood flow and vascular resistance. Macrophages have also been shown to produce nitric oxide in the body as a component of their cell killing and/or cytostatic function.
More recently it has been established that the enzyme forming nitric oxide from arginine, i.e., nitric oxide synthase, occurs in at least two distinct types, namely the constitutive forms and an inducible form. Constitutive forms are present in normal endothelial cells, neurons and some other tissues. Formation of nitric oxide by a constitutive form in endothelial cells is thought to play a role in normal blood pressure regulation. The inducible form of nitric oxide synthase has been found to be present in activated macrophages and is induced in endothelial cells and vascular smooth muscle cells, for example, by various cytokines and/or microbial products. It is thought that in sepsis or cytokine-induced shock, overproduction of nitric oxide by the inducible form of nitric oxide synthase plays an important role in the observed life-threatening hypotension. Furthermore, it is thought that overproduction of nitric oxide by the inducible form of nitric oxide synthase is a basis for insensitivity to clinically used pressor agents such as .alpha..sub.1 -adrenergic agonists in the treatment of septic or cytokine-induced shock patients. Moreover, it is thought that overproduction of nitric oxide by inducible form of nitric oxide synthase is involved in inflammation incident to an immune response.
Overproduction of nitric oxide is due either to overstimulation of a constitutive nitric oxide synthase (cNOS) or to overexpression of inducible nitric oxide synthase (iNOS). In either case, overproduction of nitric oxide is also dependent on adequate availability of arginine, the substrate of nitric oxide synthase. Arginine supply is maintained in three ways: (i) protein degradation, (ii) uptake of arginine from plasma, (iii) conversion of citrulline to arginine by pathways involving conversion of citrulline and aspartate to argininosuccinate (ASA) by argininosuccinate synthetase and conversion of ASA to arginine and fumarate by argininosuccinate lyase. In the case of iNOS, enzyme activity and overproduction of nitric oxide is also dependent on availability of required cofactors including tetrahydrobiopterin.
To date, pathological overproduction of nitric oxide has been controlled by administration of nitric oxide synthase inhibiting arginine antagonists, plasma arginine depleting enzymes and tetrahydrobiopterin induction or utilization blocking agents.